5-6

• 1. octanol/water system


  An approximation of the actual environment found in the interface between the cellular membranes and the extracellular/intracellular fluids
• Computational chemistry methods in drug design


  • Application of computational techniques and softwares to model and analyze the chemical interactions between drugs and their biological targets
• Generating pharmacophores


  Identifying the essential structural and chemical features necessary for a molecule to interact with a specific biological target and exhibit a particular biological activity
• Virtual High Throughput Screening (vHTS)

  Rapidly assessing large databases of chemical compounds in silico (using computer simulations) to identify potential lead compounds with desired biological activity
• Lead Compound Optimization


  Further optimizing a lead compound to enhance properties like potency, selectivity, and pharmacokinetics
• In Silico ADME Modeling

  Predicting the Absorption, Distribution, Metabolism, and Excretion (ADME) properties of drugs using computational methods
• Reversible effects


  Most useful drugs are held to their receptors by ionic or weaker bonds
• Irreversible effects


  Drugs that form covalent bonds with the receptor are effective and useful
• Forces involved in drug-receptor interactions

  • Hydrogen bonds
  • Ionic bonds
  • Ion-dipole and dipole-dipole interactions
  • van der Waals forces
  • Hydrophobic forces
• Ionization at physiological pH would normally occur with the carboxyl, sulfonamido, and aliphatic amino groups, as well as the quaternary ammonium group at any pH
• Differences in electronegativity between carbon and other atoms, such as oxygen and nitrogen, lead to an asymmetric distribution of electrons (dipoles) that are also capable of forming weak bonds with regions of high or low electron density, such as ions or other dipoles (dipole-dipole or ion-dipole)
• Many drugs possess groups such as carbonyl, hydroxyl, amino, and imino, with the structural capabilities of acting as acceptors or donors in the formation of hydrogen bonds
• Van der Waals forces

  Attractive forces created by the polarizability of molecules and exerted when any two uncharged atoms approach each other very closely
• Hydrophobic bond


  Attractive interactions between nonpolar regions of the receptor and the drug
• Steric factors


  • Determined by the stereochemistry of the receptor site surface and that of the drug molecules, are of primary importance in determining the nature and the efficiency of the drug-receptor interaction
• Geometric isomers


  Cis-trans isomerism or E-Z isomerism, differ in capabilities for interacting with a biological receptor, and in their distribution, metabolism and excretion of the molecules due to related changes in pKa values and rate of lipid solubility characteristics
• Conformational isomers


  Anti, eclipsed, and gauche, exist due to rotation the atoms or groups of atoms around a single bond, and differences in reactivity of functional groups or interaction with biological receptors may be caused by differences in steric requirements of the receptors

  
• Conformational flexibility of most open-chain neurohormones permits multiple biological effects to be produced by each molecule, by virtue of their ability to interact in a different and unique conformation with different biological receptors
• Optical isomerism


  Most commercial drugs are asymmetric, meaning that they cannot be divided into symmetrical halves (i.e. optically active)
• Diastereomers


  Drugs that have two or more asymmetric centers, have different physical properties
• Diastereomers


  • Ephedrine and pseudoephedrine
• Optical isomers will also have different biological properties
• Optical isomers with different biological properties

  • (-)-hyoscyamine vs (+)-hyoscyamine
  • (-)-ephedrine vs (+)-ephedrine, (+)-pseudoephedrine, (-)-pseudoephedrine
  • (-)-ascorbic acid

  
• The generic name often indicates a specific stereoisomer
• (-)-epinephrine


  Exhibits 12 to 15 times more vasoconstrictor activity than (+)-epinephrine

  
• (-)-ascorbic acid


  Contains all of the antiscorbutic properties
• Examples of drugs where the generic name indicates a specific stereoisomer

  • levodopa
  • dextroamphetamine
  • dextromethorphan
  • levamisole
  • dexmethylphenidate
  • levobupivacaine
  • dexlansoprazole
  • levothyroxine

  
• Dextrorotatory isomers in the morphine series

  Are cough suppressants with less risk of substance abuse
• Levorotatory isomers in the morphine series

  Contain the analgesic activity and significant risk of substance abuse
• Dextropropoxyphene


  Contains the analgesic activity

  
• Levo-isomer of dextropropoxyphene


  Contains antitussive activity

  
• Racemic citalopram and its S-enantiomer escitalopram

  
• Racemic omeprazole and its S-enantiomer esomeprazole

  
• Levobupivacaine


  The S-isomer of bupivacaine, has good local anesthetic activity but less cardiotoxic responses than the R-isomer
• Escitalopram


  The S-isomer of the antidepressant citalopram, the R-isomer contributes more to adverse reactions

  
• 1. S-verapamil


  Is a more active pharmacological stereoisomer than R-verapamil, but is more rapidly metabolized by the first-pass effect
• The S-enantiomer of ibuprofen contains the anti-inflammatory activity by inhibiting cyclooxygenase, while the R-isomer is converted to the S form in vivo

  
• Reasons why stereoisomers show different biological responses

  • Most receptors are asymmetric, so they can accept one stereoisomer over the other
  • Active transport mechanisms involve asymmetric carrier molecules, leading to preferential binding of one stereoisomer
  • Differences in physical properties affect the distribution of isomers between body fluids and tissues
  • Enzymes responsible for drug metabolism are asymmetric, leading to differences in biological half-lives
• The Lipinski Rule of Five states that a candidate molecule is more likely to have poor absorption or permeability if: the molecular weight exceeds 500, the calculated octanol/water partition coefficient exceeds 5, there are more than 5 H-bond donors, or there are more than 10 H-bond acceptors
• Isosterism


  The selection of structural components - steric, electronic, and solubility characteristics - that make them interchangeable in drugs of the same pharmacological class